title: Impact of genetic and clinical factors on dose requirements and quality of anticoagulation therapy in Polish patients receiving acenocoumarol: dosing calculation algorithm.
abstract: BACKGROUND
  Despite the recent emergence of new oral anticoagulants, vitamin K antagonists remain the primary therapy in patients with atrial fibrillation and the only therapy licensed for use in patients with artificial heart valves.
  
  
  OBJECTIVE
  The aim of this study was (a) to assess the impact of clinical and genetic factors on acenocoumarol (AC) dose requirements and the percentage of time in therapeutic range (%TTR) and (b) to develop pharmacogenetic-guided AC dose calculation algorithm.
  
  
  METHODS
  We included 235 outpatients of the Institute of Cardiology (Warsaw), mean age 69.3, 46.9% women, receiving AC for artificial heart valves and/or atrial fibrillation. A multiple linear-regression analysis was performed using log-transformed effective AC dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other clinical factors as independent predictors.
  
  
  RESULTS
  We identified factors that influenced the AC dose: CYP2C9 polymorphisms (P=0.004), VKORC1 polymorphisms (P<0.0001), age (P<0.0001), creatinine clearance lower than 40 ml/min (P=0.035), body mass (P=0.02), and dietary vitamin K intake (P=0.026). Clinical and genetic factors explained 49.0% of AC dose variability. We developed a dosing calculation algorithm that is, to the best of our knowledge, the first one to assess the effect of such clinical factors as creatinine clearance and dietary vitamin K intake on the AC dose. The clinical usefulness of the algorithm was assessed on separate validation group (n=50) with 70% accuracy. Dietary vitamin K intake higher than 200 mcg/day improved international normalized ratio control (%TTR 73.3±17 vs. 67.7±18, respectively, P=0.04).
  
  
  CONCLUSIONS
  Inclusion of a variety of genetic and clinical factors in the dosing calculation algorithm allows for precise AC dose estimation in most patients and thus improves the efficacy and safety of the therapy.
authors.affiliation: aOutpatient Clinic bLaboratory of Molecular Biology cDepartment of Epidemiology, Cardiovascular Diseases Prevention and Health Promotion dUnit for Screening Studies in Inherited Cardiovascular Diseases, Institute of Cardiology, Warsaw, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Wolkanin-Bartnik
authors.forename: Hanna
authors.initials: H
authors.lastname: Pogorzelska
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Szperl
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Bartnik
authors.forename: Jacek
authors.initials: J
authors.lastname: Koziarek
authors.forename: Zofia T
authors.initials: ZT
authors.lastname: Bilinska
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001281:Atrial Fibrillation / Q000188:drug therapy*; D015992:Body Mass Index; D003404:Creatinine / Q000097:blood; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D005260:Female; D005819:Genetic Markers; D014644:Genetic Variation; D005838:Genotype; D006350:Heart Valve Prosthesis; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D011044:Poland; D020641:Polymorphism, Single Nucleotide; D020246:Venous Thrombosis / Q000188:drug therapy*; D014812:Vitamin K / Q000378:metabolism; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*
chemical_list: D000925:Anticoagulants; D005819:Genetic Markers; D014812:Vitamin K; D003404:Creatinine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol